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About a third of a human being’s life is spent sleeping. Many physiological and pathological motor events (including epileptic seizures) may arise from sleep. The differential diagnosis of paroxysmal motor phenomena during sleep can therefore represent a true diagnostic challenge. When the British neurologist Sir William Richard Gowers discussed paroxysmal conditions “in the borderland of epilepsy near it, but not of it” in 1907, one chapter of his book was devoted to “sleep symptoms” and to the problem of their differentiation from epilepsy. More than a century has passed since Gowers’ invaluable contribution to the understanding of epilepsy mechanisms. However, the search for clinical parameters distinguishing epileptic attacks occurring during sleep and non-epileptic paroxysmal motor phenomena related to normal or pathological sleep continues. In the meantime, technological advances have led to a more accurate description of paroxysmal phenomena arising from sleep, providing a better definition of their different clinical and polygraphic features, and helping to explain the underlying pathophysiological mechanisms. However, prompt and correct diagnosis may still prove difficult in routine neurological practice. This chapter revisits the borderland of epilepsy, focusing on those sleep disorders, namely parasomnias and narcolepsy, that most frequently create problems in the differential diagnosis. For each condition, clinical features distinguishing it from epileptic seizures are pointed out, and an account of the current understanding of the molecular pathophysiology is provided.

Treatment for PNES must be individualized. A combination of approaches is probably the most beneficial for improvement. Treatment should not simply emphasize removing maladaptive PNES behaviour, but should also focus on learning new coping skills and removing secondary gains. If PNES persist, therapy should be re-evaluated.

Objective This study describes changes in heart rate (HR) and HR variability (HRV) related to clinical onset of seizures in nocturnal frontal lobe epilepsy (NFLE) in order to determine whether signs of autonomic activation precede onset of seizure motor manifestations, which was selected as seizure onset (SO). Further, to clarify the nature (epileptic or physiologic) of the changes in autonomic cardiac control presumed to precede SO, time-dependent variations in HR and HRV related to physiological cortical arousals associated with motor activity (phases of transitory activation, PAT) were also investigated. Methods HR and HRV spectral power, quantified by means of wavelet transform, were analyzed in relation to the onset of motor manifestations in 45 NFLE seizures and 45 PAT derived from whole night video-polysomnographic recordings of ten patients and of ten control subjects, respectively. Results Analysis of HRV showed a shift of sympathetic/parasympathetic cardiac control toward a sympathetic predominance in the 10 s immediately preceding SO, while changes in HR were evident only one second before SO. This sympathetic activation was not associated with a sleep-wake transition or changes in respiratory activity, both of which occurred concurrently with SO. Similar changes in HR and HRV were observed in the 10 s before the motor and electroencephalographic onset of PAT. Conclusions Our study demonstrates that a similar autonomic activation precedes the motor manifestations of NFLE seizures and physiological arousal. This autonomic activation could represent part of the arousal response, which could be implicated in the occurrence of both seizure and arousal motor manifestations.

Nocturnal frontal lobe epilepsy (NFLE) is a particular form of partial epilepsy in which seizures appear almost exclusively during sleep and are characterized by complex and bizarre motor behaviors. NFLE was originally described by Lugaresi and Cirignotta in 1981. The investigators coined the term nocturnal paroxysmal dystonia (NPD), underlying thepeculiarmotor pattern of theseparoxysmal nocturnal events characterized by ballistic movements, bimanual-bipedal activity, rocking axial and pelvic torsion, and/or sustained dystonic posturing or tremor of the limbs. The clinical and polysomnographic (PSG) features (stereotypicmotorpattern of the episodes, their short duration and good response to low doses of carbamazepine) suggested an epileptic origin of the events. However, in the absence of concomitant electroencephalographic (EEG) epileptic discharges, the investigators posed the question whether these episodes constituted hitherto unrecognized epileptic seizures or a new kind of movement sleep disorder. Subsequently, Tinuper and colleagues, reported two of three patients with NPD whose typical short-lasting NPD

Treatment for PNES must be individualized. A combination of approaches is probably the most beneficial for improvement. Treatment should not simply emphasize removing maladaptive PNES behaviour, but should also focus on learning new coping skills and removing secondary gains. If PNES persist, therapy should be re-evaluated.

Epilepsy and mental retardation limited to females (EFMR) is a genetic disorder that affects females but spares transmitting males. The condition is caused by protocadherin 19 mutations and is characterised by seizures beginning at around 1 year of age, frequently associated with cognitive regression at seizure onset or later. Seizures can be generalised or focal, exacerbated by febrile illnesses, and grouped in clusters. This report shows the first video-EEG recording of EFMR, in a 7-year-old female presenting peculiar ictal features. [ Published with video sequences]

Nocturnal frontal lobe epilepsy (NFLE) is characterized by seizures with complex, often bizarre, violent behaviour arising only or mainly during sleep. These unusual seizures and their occurrence during sleep are often accompanied by normal EEG tracings and neuroradiological findings, making it difficult to distinguish NFLE seizures from other non-epileptic nocturnal paroxysmal events, namely parasomnias. NFLE was described for the first time in 1981, but, as its epileptic origin was controversial, the condition was called nocturnal paroxysmal dystonia. Even though many aspects of parasomnias and NFLE have been clarified in the last two decades, the problem of differential diagnosis remains a challenge for clinicians. This paper discusses some controversial points still under debate. The difficulties in distinguishing nocturnal epileptic seizures from parasomnias reflect just one aspect of the intriguing issue of the pathophysiological relationships between all types of paroxysmal motor behaviours during sleep.

Since the first descriptions of Nocturnal Frontal Lobe Epilepsy (NFLE) many theories have been proposed to explain its pathophysiological mechanisms. The aim of this paper is to formulate a tentative hypothesis designed to unify the clinical, anatomo-physiological, and genetic aspects underlying this condition. According to this hypothesis, NFLE is due to a disorder in the thalamocortical circuit involved in the arousal mechanism. Other cortical-networks involving the limbic system may explain, for instance, primitive behaviors. The role of the cholinergic system and related pathways in the pathogenesis of nocturnal seizures and parasomnias is also discussed.

A nationwide telephone interview was conducted on a random sample of Italian schoolteachers (300 from primary and 300 from secondary schools) to ascertain knowledge and attitudes about epilepsy. Included were 516 women and 84 men aged 22 to 70 years. Thirty-seven percent of the teachers believed epilepsy starts only in childhood, 55% considered it hereditary, 46.8% declared it incurable, and only 10.5% knew surgery is a therapeutic option. Thirty-three percent considered epilepsy a moderate-to-strong limitation for marriage, 24.6% for having children, 39.7% for regular employment, and 32.8% for sports and leisure activities. Among the teachers, 66.4% declared they were unable to manage a seizing child, 24.7% were convinced that epilepsy impairs learning, 26.0% believed that it carries mental/behavioral alterations, and 36.4% thought it requires support at school. Differences in knowledge and attitudes were predicted by teachers' age and area of residency. There were no major differences between teachers and the Italian population in their knowledge and attitudes.

Objectives To measure the accuracy of anamnestic features collected during clinical history for the diagnosis of nocturnal frontal lobe epilepsy (NFLE). Methods A case-control diagnostic study. Participants included a case group of people with ascertained target disease (NFLE group) and a control group of people with sleep disorders potentially confounding for NFLS (NOT-NFLE group), defined by means of a consensus procedure among experts (panel diagnosis as reference standard). Two major clinical patterns defining the semeiology of the epileptic event (i.e. dystonic, DP, and/or hyperkinetic pattern, HP), and 13 additional minor features were identified, formulated as questions, and telephonically administered to NFLE and NOT-NFLE groups by a trained doctor blinded to the final diagnosis. The diagnostic accuracy of each characteristic was tested against the reference standard. Results Out of 262 selected subjects, 101 were recruited; 42 were NFLE and 59 NOT-NFLE. A positive history of DP or HP had a sensitivity of 59.5% and a specificity of 91.5%, irrespective of the other minor anamnestic features. The anamnestic model improved, with a sensitivity of 59.5% and specificity of 96.6%, if at least one of the following four minor anamnestic features was added: (a) duration less than two minutes, (b) unstructured vocalization during the episode, (c) experience of an aura preceding the motor attack, and (d) a history of tonic-clonic seizures during sleep. Conclusions The present study disclosed two major anamnestic patterns and four minor features that we called SINFLE, with unsatisfactory sensitivity but high specificity. These patterns could be the basis for developing future NFLE diagnostic criteria and to quantify the diagnostic accuracy of elements usually collected in the clinical history.

Accelerated long term forgetting (ALF) is a characteristic cognitive aspect in patients affected by temporal lobe epilepsy that is probably due to an impairment of memory consolidation and retrieval caused by epileptic activity in hippocampal and parahippocampal regions. We describe a case of a patient with TLE who showed improvement in ALF and in remote memory impairment after an anterior left temporal pole lobectomy including the uncus and amygdala. Our findings confirm that impairment of hippocampal functioning leads to pathological ALF, whereas restoration of hippocampal functioning brings ALF to a level comparable to that of controls.

Syndromic classification is important in patients with epilepsy to evaluate the prognosis as soon as possible, but unfortunately a classification may be difficult even after a relatively long follow-up period. We describe the case of a young boy who presents a non-symptomatic focal epilepsy with occipital spikes and waves. Epilepsy onset took place at 3 years of age characterized by different seizures types. During evolution (4 years) complex motor seizures with autonomic features persisted resistant to AED. Clinical picture has some features currently described in Panayiotopoulos syndrome, an idiopathic childhood focal epilepsy, but other features (semiology frequency and length of seizures, partial response to treatment) do not support this hypothesis. The description of “borderline” patients, according to typical classified epileptic syndromes, can be useful for prognostic and treatment suggestions.

The KCNAB1 gene is a candidate susceptibility factor for lateral temporal epilepsy (LTE) because of its functional interaction with LGI1, the gene responsible for the autosomal dominant form of LTE. We investigated association between polymorphic variants across the KCNAB1 gene and LTE. The allele and genotype frequencies of 14 KCNAB1 intronic SNPs were determined in 142 Italian LTE patients and 104 healthy controls and statistically evaluated. Single SNP analysis revealed one SNP (rs992353) located near the 3'end of KCNAB1 slightly associated with LTE after multiple testing correction (odds ratio=2.25; 95\% confidence interval 1.26-4.04; P=0.0058). Haplotype analysis revealed two haplotypes with frequencies higher in cases than in controls, and these differences were statistically significant after permutation tests (Psim=0.047 and 0.034). One of these haplotypes was shown to confer a high risk for the syndrome (odds ratio=12.24; 95\% confidence interval 1.32-113.05) by logistic regression analysis. These results support KCNAB1 as a susceptibility gene for LTE, in agreement with previous studies showing that this gene may alter susceptibility to focal epilepsy.

The aim of this study was to describe in detail the neurological features of nine patients carrying the recently reported microduplication at Xp11.22-11.23. Clinical and neurological examination, brain magnetic resonance imaging (except for two patients), electroencephalography and a neuropsychological assessment specific for language disturbances were performed in nine patients with microduplication at Xp11.22-11.23, disclosed by comparative genomic hybridisation array. Six patients were familial cases belonging to three unrelated pedigrees and three were sporadic cases. The patients had the following characteristics: mild dysmorphic facial features (except for two patients), mental retardation with moderate to severe global language deterioration, electroencephalographic epileptiform discharges during wakefulness and especially during sleep or electrical status epilepticus during slow sleep in younger cases, and negative brain magnetic resonance imaging. The main clinical features of this new microduplication syndrome were mild facial dysmorphisms, from increased electroencephalogram abnormalities during sleep to electrical status epilepticus during slow sleep, and mental retardation mainly involving language function in the absence of detectable brain lesions. In the absence of detectable brain lesions, speech delay may be associated with electrical status epilepticus during slow sleep or, alternatively, related to abnormal brain expression of a dosage-sensitive gene contained within the duplication region.

Arousal Disorders (AD) are motor behaviours arising from NREM sleep. They comprise a spectrum of manifestations of increasing complexity from confusional arousal to sleep terror to sleepwalking. AD usually appear in childhood with a low frequency of episodes and spontaneously disappear before adolescence. The advent of video-polysomnography disclosed the existence of other phenomena alongside AD, in particular nocturnal frontal lobe seizures, requiring a differential diagnosis from AD. History-taking is usually sufficient to establish a correct diagnosis of AD even though viewing the episodes is essential for the clinician to distinguish the different motor events. Videopolysomnographic recording in a sleep laboratory is not always necessary and homemade video-recordings are useful to capture events closest to real life episodes.

Three patients complained of paroxysmal motor attacks during sleep. Videopolygraphic recordings showed that motor activity could be divided into events of increasing behavioural complexity. Simpler motor events often represented the initial fragment of more complex attacks. Clinical features suggested the attacks represented frontal lobe epileptic seizures. The attacks recurred during NREM sleep with a periodic repetition every 20-60 sec. This periodicity could be related to the analogous physiological oscillation during light sleep and the periodicity of K complexes, exerting a facilitating influence upon epileptic mechanisms.

Seizure response and alerting behaviour may spontaneously develop in dogs living with children or adults with epilepsy. Some dogs can also be reliably trained to respond and anticipate seizures. We describe the case of a dog, not previously trained for assistance work, showing complex seizure response behaviour. This is the first release of a home video recording of a dog reacting to its owner's seizure.

A nationwide survey was performed in Italy to assess awareness and attitudes of the public about epilepsy. Knowledge about epilepsy, its clinical features, and attitudes towards its social/individual implications were tested in a telephone interview. Included were 819 women and 737 men aged 18+ years. 93.4% declared they knew epilepsy, 56.6% knew a person with epilepsy, and 45.1% saw someone seizing. Only 29.2% gave an exact estimate of the prevalence of the disease. 50.4% were unaware of the causes, 56.1% indicated that epilepsy was a psychological/psychiatric disease, 36.5% a form of insanity, and 4.1% an evil spirit possession. Epilepsy was incurable according to 35.5%. Moderate-to-severe restrictions to driving, regular employment, military career, and leisure activities were suggested by 79.8, 57.0, 71.1, and 57.6%. Limitations included marriage and procreation for 46.2 and 38.7%. Knowledge and attitudes varied with education, age and gender. These findings are partly in keeping with other worldwide reports.

Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8-9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.

The authors retrospectively analyzed and compared seizure outcome in a series of 28 patients with temporomesial glioneuronal tumors associated with epilepsy who underwent 1 of 2 different epilepsy surgery procedures: lesionectomy or tailored resection.The 28 patients were divided into 2 groups, with 14 cases in each group. In Group A, surgery was limited to the tumor (lesionectomy), whereas Group B patients underwent tailored resection involving removal of the tumor and the epileptogenic zone as identified by a neurophysiological noninvasive presurgical study.In Group A (10 male and 4 female patients) the interval between onset of seizures and surgery ranged from 1 to 33 years (mean 10.6 years). Patients' ages ranged from 3 to 61 years (mean 23.1 years). The epileptogenic lesion was on the left side in 6 patients and the right in 8 patients. Mean follow-up was 9.8 years (range 6.5-15 years). The Engel classification system, used to determine postoperative seizure outcome, showed 6 patients (42.8%) were Engel Class I and 8 (57.1%) were Engel Class II. In Group B (6 male and 8 female patients) the interval between onset of seizures and surgery ranged from 0.5 to 25 years (mean 8.6 years). Patients' ages ranged from 3 to 48 years (mean 22.3 years). The tumor and associated epileptogenic area was on the right side in 8 patients and the left in 6 patients. Mean follow-up duration was 3.5 years (range 1-6.5 years). Postoperative seizure outcome was Engel Class I in 13 patients (93%) and Engel Class II in 1 (7.1%).The authors' results demonstrate a better seizure outcome for temporomesial glioneuronal tumors associated with epilepsy in patients who underwent tailored resection rather than simple lesionectomy (p = 0.005). For temporomesial glioneuronal tumors associated with epilepsy, performing a presurgical noninvasive neurophysiological study intended to identify the epileptogenic zone is necessary for planning a tailored surgery. Using this surgical strategy, the presence of temporomesial glioneuronal tumors constitutes a predictive factor of excellent seizure outcome, and therefore surgical treatment can be offered early to avoid both the consequences of uncontrolled seizures as well as the side effects of pharmacological therapy.

Summary Purpose: To disclose clinical, electrophysiologic, and neuroradiologic factors correlated to prognosis in patients with mesial temporal lobe epilepsy (MTLE). Methods: One hundred thirty-six MTLE patients were studied for family history, clinical characteristics, instrumental data [electroencephalography (EEG), video-EEG, neuroimaging], and outcome. The population was divided into drug-resistant (DR: 108 patients, 79.4%) and non–drug-resistant (NDR: 28 patients, 20.6%) groups; all variables were analyzed in the two groups. Results: The comparison between the two groups shows a relation between resistance to therapy and febrile seizures (FS) (DR 43.5% vs. NDR 17.8%, p = 0.008), mesial temporal sclerosis (MTS) (DR 64.8% vs. NDR 32.1%, p = 0.0025), early age at seizure onset (DR 23.1% vs. NDR 3.6% p = 0.0160), and epileptiform interictal abnormalities (DR 89.7% vs. NDR 68%, p = 0.010). FS were more frequent in patients with MTS than in patients without (46.28% vs. 26.3%, p = 0.0199). Sixty-nine patients underwent surgery and 85.3% of them had a good outcome. Conclusion: MTLE is a heterogeneous syndrome. Establishing the factors responsible for and associated with drug resistance is important for therapeutic purposes, as prompt diagnosis of drug resistance must lead to early surgical management. This study shows that FS, MTS, early age at seizure onset, and epileptiform interictal abnormalities are negative prognostic factors and that FS are related to MTS.

Pilomotor seizures are rarely reported in the literature. Only 16 cases have been described until now, and seizures were recorded on EEG in only four patients. A 67-year-old woman has had four nocturnal tonic-clonic attacks since the age of 63. At the age of 67, brief, very frequent episodes appeared, characterized by a sudden feeling of "fuzziness" all over her body accompanied by diffuse piloerection. Several seizures have been recorded during video-polygraphic monitoring, showing a right temporal discharge and transient increase in arterial blood pressure without tachycardia. This patient's seizures demonstrate a "pure" form of autonomic dysfunction.

Limbic encephalitis (LE) is a neurological syndrome that may present in association with cancer, infection, or as an isolate clinical condition often accompanying autoimmune disorders. Here we have characterized the clinical and laboratory features of two patients presenting with subacute onset, and chronic evolution, of anterograde amnesia and drug-resistant epilepsy associated with thyroid autoimmunity and in absence of tumoral pathology despite long follow-up. Antibodies against onconeural antigens, voltage gated potassium channel and glutamate receptors, which may accompany paraneoplastic as well as non-paraneoplastic LE, were negative. However, biochemical studies showed high titers, and sustained intrathecal synthesis, of antibodies directed against neuronal glutamic acid decarboxylase (GAD). In one patient, plasma exchange determined a dramatic improvement of the neurological deficits along with the decrease of autoantibodies.

Epidemiological surveys on status epilepticus (SE) in adults in two Italian areas (Bologna and Lugo di Romagna) disclosed a major difference in 30-day case fatality (33% versus 7 %). Since suboptimal management was hypothesised in the first site, we compared the quality of treatment in the two cohorts and examined its contribution to prognosis.The Bologna and Lugo di Romagna cohorts of adults with incident SE were included. Patients with post-anoxic encephalopathy were excluded. Quality of treatment was independently classified by two experts. Clinical and treatment features were compared in the two sites. The contribution of variables collected to the 30-day case fatality was explored through multivariate logistic analysis in the whole group of patients.Fifty-seven patients were included. No differences were observed between Bologna and Lugo di Romagna either in clinical features or the time of management. The quality of global drug treatment significantly differed in disfavour of Bologna (p = 0.044). Independent predictors of a worse 30-day case fatality in the whole group of patients were the onset of SE in hospital (OR 9.67, p = 0.0095) and the poor global quality of treatment (partially correct versus correct OR 3.59, p = 0.55, and incorrect versus correct OR 21.09, p = 0.0084). By subgroup analysis, the site of onset factor encompasses the aetiologic background of patients.In addition to previously known prognostic factors, epidemiological comparison of mortality rates of SE between different regions must also consider the quality of treatment.

Autosomal dominant lateral temporal epilepsy (ADTLE) is a genetically transmitted epileptic syndrome characterized by focal seizures with predominant auditory symptoms likely originating from the lateral region of the temporal lobe. Mutations in coding region or exon splice sites of the leucine-rich, glioma-inactivated 1 (LGI1) gene account for about 50\% of ADLTE families. De novo LGI1 mutations of the same kind have also been found in about 2.5\% of non-familial cases with idiopathic partial epilepsy with auditory features (IPEAF). In both conditions, mutations in the LGI1 promoter region have not been reported. We sequenced the minimal promoter region of LGI1 in the probands of 16 ADLTE families and in 104 sporadic IPEAF patients and no mutations clearly linked to the disease were found. However, two polymorphisms, -500G>A and -507G>A, with potential functional implications were identified and analysed in the cohort of sporadic IPEAF patients but their frequencies did not differ from those found in a control population of similar age, gender and geographic origin. We also analysed in our study population the GABA(B) receptor 1 c.1465G>A and the prodynorphin promoter 68-bp repeat polymorphisms, previously associated with temporal lobe epilepsy. None of these polymorphisms showed a significant association with IPEAF, whereas a tendency towards association with the prodynorphin low expression (L) alleles was found in the small group of ADLTE index cases, in agreement with previous studies suggesting that this polymorphism is a susceptibility factor in familial forms of temporal lobe epilepsy.

In order to study the correlation between central nervous system (CNS) involvement and EEG abnormalities in HIV infection we studied 100 consecutive HIV patients. Patients were divided into 4 groups; Group I: 42 neurologically asymptomatic subjects; Group II: 6 patients with peripheral neuropathies; Group III: 28 patients with AIDS Dementia Complex; Group IV: 24 patients with secondary CNS involvement. The results of this study emphasize that abnormal EEGs are correlated with CNS involvement. Neurologically asymptomatic patients showed no abnormal tracings, but the presence of borderline EEGs (33%) in asymptomatic patients should be evaluated prospectively.

Mutations in the LGI1 gene are linked to autosomal dominant lateral temporal epilepsy (ADTLE) in about half of the families tested, suggesting that ADLTE is genetically heterogeneous. Recently, the Lgi1 protein has been found associated with different protein complexes and two distinct molecular mechanisms possibly underlying ADLTE have been hypothesized: the one recognizes Lgi1 as a novel subunit of the presynaptic Kv1 potassium channel implicated in the regulation of channel inactivation, the other suggests that Lgi1 acts as a ligand that selectively binds to the postsynaptic receptor ADAM22, thereby regulating the glutamate-AMPA neurotransmission. Both mechanisms imply that LGI1 mutations result in alteration of synaptic currents, though of different types. Since their protein products have been found associated with Lgi1, the Kv1 channel subunit genes KCNA1, KCNA4, and KCNAB1 and ADAM22 can be considered strong candidates for ADLTE. We sequenced their coding exons and flanking splice sites in the probands of 9 carefully ascertained ADLTE families negative for LGI1 mutations. We failed to detect any mutation segregating with the disease, but identified several previously unreported polymorphisms. An association study of four non-synonymous variants (three found in ADAM22, one in KCNA4) in a population of 104 non-familial lateral temporal epilepsy cases did not show any modification of susceptibility to this disorder. Altogether, our results suggest that neither ADAM22 nor any of the three Kv1 channel genes are major causative genes for ADLTE.

Summary: Purpose: To assess the comparative effectiveness, efficacy, and tolerability of lamotrigine (LTG) and sustained-release carbamazepine (CBZ) in the treatment of newly diagnosed epilepsy in the elderly. Methods: Patients aged 65 years or older, who had experienced at least two unprovoked partial and/or generalized tonic–clonic seizures, were randomized to receive LTG (n = 93) or CBZ (n = 92) according to a multicenter double-blind, parallel-group design. Trial duration was 40 weeks and included a 4-week dose escalation followed by a maintenance phase during which dosages could be adjusted according to response. Initial, maintenance and maximum dosages were 25 mg, 100 mg, and 500 mg per day for LTG, and 100 mg, 400 mg, and 2,000 mg per day for CBZ, respectively. The primary end point was retention in the trial. Results: In the LTG group, 68 patients (73%) completed the 40-week study period compared with 61 (67%) in the CBZ group, a nonsignificant difference. Time to withdrawal from any cause did not differ between groups (p = 0.34). The number of subjects who completed the 40-week period and were seizure free in the last 20 weeks was 48 (52%) in the LTG group and 52 (57%) in the CBZ group. Adverse events leading to withdrawal occurred in 13 (14%) subjects in the LTG group and 23 (25%) subjects in the CBZ group. Conclusion: LTG and CBZ showed comparable effectiveness, with a trend for higher seizure-free rates for CBZ and better tolerability for LTG. Differences in outcome compared with previous trials may be related to different dosing rates and use of a sustained-release formulation for CBZ.

Nocturnal frontal lobe seizures (NFLS) show one or all of the following semeiological patterns: (1) paroxysmal arousals (PA: brief and sudden recurrent motor paroxysmal behavior); (2) hyperkinetic seizures (HS: motor attacks with complex dyskinetic features); (3) asymmetric bilateral tonic seizures (ATS: motor attacks with dystonic features); (4) epileptic nocturnal wanderings (ENW: stereotyped, prolonged ambulatory behavior).To estimate the interobserver reliability (IR) of video-recording diagnosis in patients with suspected NFLS among sleep medicine experts, epileptologists, and trainees in sleep medicine.Sixty-six patients with suspected NFLS were included. All underwent nocturnal video-polysomnographic recording. Six doctors (three experts and three trainees) independently classified each case as "NFLS ascertained" (according to the above specified subtypes: PA, HS, ATS, ENW) or "NFLS excluded". IR was calculated by means of Kappa statistics, and interpreted according to the standard classification (0.0-0.20 = slight agreement; 0.21-0.40 = fair; 0.41-0.60 = moderate; 0.61-0.80 = substantial; 0.81-1.00 = almost perfect).The observed raw agreement ranged from 63% to 79% between each pair of raters; the IR ranged from "moderate" (kappa = 0.50) to "substantial" (kappa = 0.72). A major source of variance was the disagreement in distinguishing between PA and nonepileptic arousals, without differences in the level of agreement between experts and trainees.Among sleep experts and trainees, IR of diagnosis of NFLS, based on videotaped observation of sleep phenomena, is not satisfactory. Explicit video-polysomnographic criteria for the classification of paroxysmal sleep motor phenomena are needed.

Summary: Purpose: Nocturnal frontal lobe epilepsy (NFLE) may be associated with sleep fragmentation and reduced sleep efficiency. Daytime sleepiness and disturbed sleep quality have been reported in some patients. We investigated the occurrence of daytime sleepiness-related symptoms and subjective sleep quality in patients with NFLE in comparison with matched controls. Methods: Patients with NFLE at a single epilepsy center and matched controls randomly selected from the general population self-administered questionnaires on daytime sleepiness-related symptoms and subjective sleep quality [Epworth sleepiness scale (ESS), Bologna questionnaire on sleepiness-related symptoms (BQS), Berlin questionnaire]. Results: Thirty-three patients with NFLE and 27 controls were enrolled. “Tiredness after awakening” and “spontaneous mid-sleep awakenings” were more frequent in NFLE patients than in controls (36.4% versus 11.1%, p = 0.04, and 50.0% versus 22.2%, p = 0.03). The frequency of excessive daytime sleepiness (EDS) did not differ between groups. Posthoc analysis showed that patients with a complaint of “midsleep awakenings” had higher ESS and BQS scores than those without (7.3 versus 4.3, p = 0.004, and 5.0 versus 2.2, p = 0.001, respectively) and more frequent “tiredness after awakening” (56.3% versus 18.8%, p = 0.03). Conclusions: Patients with NFLE have no pathological level of EDS with respect to controls. However, daytime sleepiness-related symptoms could be more frequent in a subgroup of patients with subjective disturbed sleep quality, irrespective of the perceived frequency of seizures.

Autosomal dominant lateral temporal epilepsy (ADTLE) is a syndrome characterized by ictal auditory phenomena suggesting a lateral temporal lobe seizure onset and is associated with mutations in the leucine-rich, glioma inactivated 1 (LGI1) gene.1,2 The structure of the LGI1 protein includes, in the N-terminal portion, three leucine-rich repeats (LRR). The function of LGI1 and the mechanisms underlying epilepsy in patients with LGI1 mutations are not established. However, LGI1 is involved in the control of survival of neuroblastoma cell lines.3 This feature and the structural homology between LGI1 and other LRR proteins essential for the development of the CNS3 make it conceivable that LGI1 mutations could imply some structural abnormalities of the lateral temporal lobe as the substratum underlying partial epilepsy in ADTLE. Neuropathologic data are lacking and conventional MRI studies failed to show consistent findings in ADTLE.1,2 Voxel-based analyses enable detection of subtle regional differences in MR images.4,5 ### Methods. We performed voxel-based analyses of T1-weighted, diffusion-tensor, and magnetization transfer (MT) images of the brain in 8 patients (3 women and 5 men, mean age 49 ± 13 years) with ADTLE and LGI1 mutations and 24 healthy control subjects (14 women and 10 men, mean …

Telephone-induced seizures have recently been described as a distinct form of idiopathic reflex epilepsy in which seizures are repeatedly and exclusively triggered by answering the telephone.1 Typical auras consist of auditory or vertiginous symptoms and the inability to speak or understand spoken voices. These features, along with specific EEG ictal findings in one patient, suggest that this condition involves the lateral temporal area.1 Autosomal dominant partial epilepsy with auditory features (ADPEAF; OMIM 600512), or autosomal dominant lateral temporal epilepsy (ADLTE), is a rare familial partial epilepsy syndrome with onset in childhood/adolescence and benign evolution.2,3 The hallmark of the syndrome consists of the presence of typical auditory auras or ictal aphasia in most affected family members, sometimes triggered by environmental sounds and noises. ADPEAF is associated in about half of the families with mutations of the leucine-rich, glioma-inactivated 1 ( LGI1)/Epitempin gene,3,4 the function of which is still unclear. Earlier we described a series of sporadic patients with idiopathic partial epilepsy with auditory features (IPEAF) who were clinically indistinguishable from ADPEAF cases5 …

Seizures, namely in certain epileptic conditions, may be precipitated by sleep. Nocturnal frontal lobe epilepsy seizures, characterized by bizarre motor behaviour and autonomic activation, appear almost exclusively during sleep. The differential diagnosis between this condition and sleep-related non-epileptic paroxysmal motor phenomena, in particular the parasomnias, is arduous. Moreover, accepted criteria for the diagnosis of nocturnal frontal lobe seizures are lacking and even ictal scalp EEG recording could fail to disclose paroxysmal abnormalities. The clinical and polygraphic features of the different types of seizures in nocturnal frontal lobe epilepsy and of the more common non-epileptic paroxysmal events during sleep are described. The main differentiating features characterizing nocturnal frontal seizures are: onset at any age, several attacks per night at any time during the night, brief duration (s) with stereotyped motor pattern. As video-polysomnographic recordings of the attack, the gold-standard for diagnosis, are expensive and not readily available everywhere, home-made video recordings may be helpful. Further investigations on pathophysiology, genetics and epidemiology are needed to clarify the relationship between epileptic and non-epileptic sleep related paroxysmal phenomena.

Objective: To identify novel genes implicated in epilepsy with auditory features (EAF) in phenotypically heterogeneous families with unknown molecular basis. Methods: We identified 15 probands with EAF in whom an LGI1 mutation had been excluded. We performed electroclinical phenotyping on all probands and available affected relatives. We used whole-exome sequencing (WES) in 20 individuals with EAF (including all the probands and 5 relatives) to identify single nucleotide variants, small insertions/deletions, and copy number variants. Results: WES revealed likely pathogenic variants in genes that had not been previously associated with EAF: a CNTNAP2 intragenic deletion, 2 truncating mutations of DEPDC5, and a missense SCN1A change. Conclusions: EAF is a clinically and molecularly heterogeneous disease. The association of EAF with CNTNAP2, DEPDC5 ,a ndSCN1A mutations widens the phenotypic spectrum related to these genes. CNTNAP2 encodes CASPR2, a member of the voltage-gated potassium channel complex in which LGI1 plays a role. The finding of a CNTNAP2 deletion emphasizes the importance of this complex in EAF and shows biological convergence. Neurol Genet 2015;1:e5; doi

To evaluate whether vagus nerve stimulation (VNS) as adjunct to best medical practice (VNS + BMP) is superior to BMP alone in improving long-term health-related quality of life (HRQoL).PuLsE (Open Prospective Randomized Long-term Effectiveness) was a prospective, randomized, parallel-group, open-label, and long-term effectiveness study (conducted at 28 sites in Europe and Canada). Adults with pharmacoresistant focal seizures (n = 112) received VNS + BMP or BMP (1:1 ratio). Medications and VNS parameters could be adjusted as clinically indicated for optimal seizure control while minimizing adverse effects. Primary endpoint was mean change from baseline HRQoL (using Quality of Life in Epilepsy Inventory-89 total score; QOLIE-89). Secondary endpoints included changes in seizure frequency, responder rate (≥50% decrease in seizure frequency), Centre for Epidemiologic Studies Depression scale (CES-D), Neurological Disorders Depression Inventory-Epilepsy scale (NDDI-E), Clinical Global Impression-Improvement scale (CGI-I), Adverse Event Profile (AEP), and antiepileptic drug (AED) load. The study was prematurely terminated due to recruitment difficulties prior to completing the planned enrollment of n = 362. Results for n = 96 who had baseline and at least one follow-up QOLIE-89 assessment (from months 3-12) were included in this analysis. Mixed model repeated measures (MMRM) analysis of variance was performed on change from baseline for the primary and secondary endpoints.Significant between-group differences in favor of VNS + BMP were observed regarding improvement in HRQoL, seizure frequency, and CGI-I score (respective p-values0.05, 0.03, and 0.01). More patients in the VNS + BMP group (43%) reported adverse events (AEs) versus BMP group (21%) (p = 0.01), a difference reflecting primarily mostly transient AEs related to VNS implantation or stimulation. No significant difference between treatment groups was observed for changes in CES-D, NDDI-E, AEP, and AED load.VNS therapy as a treatment adjunct to BMP in patients with pharmacoresistant focal seizures was associated with a significant improvement in HRQoL compared with BMP alone. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Summary: Purpose: Cortical tremor, a form of rhythmic cortical myoclonus (rhythmic CM), and epilepsy have been described in families with autosomal dominant inheritance. Linkage analyses revealed two putative loci on chromosome 2p and 8q. Clinical photosensitivity was not a prominent feature in such families. We describe a large Italian family with rhythmic CM, photosensitivity, and epilepsy. Methods: Twenty-three individuals of a five-generation family were studied. Linkage analyses for the loci on chromosome 2p11.1 and 8q23.3 were performed. Results: Of the 23 studied family members, 16 were affected. Rhythmic CM of childhood onset was present in all 16 individuals (onset ranging from 3 to 12 years), was associated with photic-induced myoclonic jerks in seven, and with epileptic seizures in six (onset ranging from 23 to 34 years). Five children of the V generation manifested also episodes of arousal with generalized tremor in early infancy (“tremulous arousals”). Jerk-locked back-averaging of rhythmic CM of six affected individuals, documented a premyoclonic EEG correlate. C-reflex at rest was present in two affected adults. Linkage analyses excluded mapping to the 2p11.1 and 8q23.3 loci. Conclusions: Clinical variability and severity of the phenotypes in this family are in line with those of previously described pedigrees with autosomal dominant cortical myoclonus and epilepsy. In this family, a progression of symptoms was found: rhythmic CM and tremulous arousals occurred in childhood, whereas visually induced manifestations and epileptic seizures occurred during adolescence–adulthood. Exclusion of linkage to the two known loci is consistent with genetic heterogeneity of such familial clustering of symptoms.

The definitive version is available at http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T34-4JYTRWV-1&_user=4221266&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000048559&_version=1&_urlVersion=0&_userid=4221266&md5=efd2685823995c3ad94101782def140b, Mutations in the LGI1/Epitempin gene cause autosomal dominant lateral temporal lobe epilepsy (ADLTE), a partial epilepsy characterized by the presence of auditory seizures. However, not all the pedigrees with a phenotype consistent with ADLTE show mutations in LGI1/Epitempin, or evidence for linkage to the 10q24 locus. Other authors as well as ourselves have found an internal repeat (EPTP, pfam# PF03736) that allowed the identification of three other genes sharing a sequence and structural similarity with LGI1/Epitempin. In this work, we present the sequencing of these genes in a set of ADLTE families without mutations in both LGI1/Epitempin and sporadic cases. No analyzed polymorphisms modified susceptibility in either the familial or sporadic forms of this partial epilepsy., This work is funded by a grant from the Ministerio de Educación y Ciencia (SAF2002-00060) to JP-T, from the Ilundain Fundazioa to ALdM, JJP and JFMM, from Telethon-Italy (GGP02339) to CN and RM, and from the Commissione Genetica, Lega Italiana Contro l’Epilessia (LICE) to RM and CN. JP-T and CN are recipients of a collaborative CSIC-CNR grant (2003IT0018). JP-T is part of the Grupos de Excelencia of the Generalitat Valenciana (GRUPOS03/015).